Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition
Open accessAbstract
Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
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Several groups have reported that resistance clones are not preexisting but occur via epigenetic adaptation of drug-tolerant persisters whereby some undergo further evolution to acquire genetic resistance mechanisms.
“Several groups have reported that resistance clones are not preexisting but occur via epigenetic adaptation of drug-tolerant persisters whereby some undergo further evolution to acquire genetic resistance mechanisms (45–47).”
A characteristic feature of drug-tolerant cells is evasion of drug-induced apoptosis.
“A characteristic feature of drug-tolerant cells is evasion of drug-induced apoptosis [25].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
In the authors' study, 5-10% of PC9 pools developed rapid resistance due to acquisition of the EGFRT790M resistance mutation as early as 2 weeks after initiating gefitinib treatment.
“This resulted in two treatment outcomes: a minority of pools (5–10%) developed rapid resistance due to acquisition of the EGFRT790M resistance mutation as early as 2 weeks after initiating drug treatment (early-resistant clones)”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
Lineage tracing with DNA barcoding confirmed that early-resistant clones were derived from rare pre-existing EGFRT790M-positive cells in the parental PC9 cell line.
“Lineage tracing with DNA barcoding confirmed that the early-resistant clones were derived from rare pre-existing EGFRT790M-positive cells that existed in the parental PC9 cell line.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
The drug-tolerant persister state can serve as a cellular reservoir from which clones that evolve bona fide drug-resistance mechanisms can emerge.
“These tumor subpopulations can evade strong selective drug pressure by entering this drug-tolerant “persister” state which can then serve as a cellular reservoir from which clones that evolve bona fide drug-resistance mechanisms can emerge [25,26].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
PC9 single-cell cultures that did not harbor pre-existing EGFRT790M cells eventually gave rise to EGFRT790M or other genomic mechanisms of resistance when treated continuously, demonstrating de novo evolution of drug resistance mechanisms from persisters.
“On the other hand, PC9 single-cell cultures that did not harbor pre-existing EGFRT790M cells eventually gave rise to EGFRT790M or other genomic mechanisms of resistance when treated with EGFR inhibitor continuously for extended periods of time, demonstrating de novo evolution of drug resistance mechanisms from persisters.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
The drug-tolerant persister state may comprise a reservoir of cells from which heterogeneous drug-resistance mechanisms can evolve.
“Thus, these studies suggest that the drug-tolerant persister state may comprise a reservoir of cells from which heterogeneous drug-resistance mechanisms can evolve.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
In the authors' study, most PC9 pools initially underwent a dramatic drug response followed by slow expansion of a small subpopulation of surviving, drug-tolerant cells, and finally development of full drug resistance up to a year later.
“while most pools initially underwent a dramatic initial drug response followed by slow expansion of a small subpopulation of surviving, drug-tolerant cells, and finally (up to a year later) the development of full drug resistance (late-resistant clones).”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
Clinical mechanisms of acquired resistance can occur by evolution of drug-tolerant persister cells during long term drug exposure.
“Subsequently, work by our group and others showed that clinical mechanisms of acquired resistance can occur by evolution of drug-tolerant persister cells during long term drug exposure [25,26].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
Resistant clones that evolved from drug-tolerant cells and retained a partial mesenchymal phenotype showed decreased apoptotic response to third-generation EGFR inhibitors, and treatment with navitoclax restored sensitivity.
“Similarly, resistant clones that evolved from drug-tolerant cells and retained a partial mesenchymal phenotype showed decreased apoptotic response to third-generation EGFR inhibitors, and treatment with navitoclax restored sensitivity [25].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [25]
Hata et al. identified patterns of resistance development characterised by pre-existing drug-resistant EGFR T790M-positive clones as well as de novo acquisition of the EGFR T790M mutation within initially EGFR T790M-negative drug-tolerant cells.
“By the monitoring of the development of large numbers of resistant clones in parallel, authors were able to identify patterns characterised by pre-existing drug-resistant EGFRT790M-positive clones as well as the de novo acquisition of the EGFRT790M mutation within initially EGFRT790M-negative drug-tolerant cells.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [31]
Treatment with navitoclax, an inhibitor of BCL-xL and BCL-2, restored sensitivity in models of resistance to third-generation EGFR inhibitors.
“However, treatment with navitoclax, an inhibitor of the antiapoptotic factors BCL-xL and BCL-2, restored sensitivity.31”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [31]
Recent in vitro cell line data suggest that T790M mutation can arise de novo as a new mutation in tumor cells that survive during TKI therapy.
“recent in vitro data using cell line models have suggested that T790M mutation could also arise de novo as a new mutation in tumor cells that survive (referred to as a drug-tolerant population) during TKI therapy.102”
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- Authors
- Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., Siravegna, G., Hu, H., Raoof, S., Lockerman, E., Kalsy, A., Lee, D., Keating, C. L., Ruddy, D. A., Damon, L. J., Crystal, A. S., Costa, C., Piotrowska, Z., Bardelli, A., Iafrate, A. J., Sadreyev, R. I., Stegmeier, F., Getz, G., Sequist, L. V., Faber, A. C., & Engelman, J. A.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Candiolo Cancer Institute (IT)
- Virginia Commonwealth University (US)
- Corresponding author
- Engelman, Jeffrey A
- ORCID
- Hata, Aaron N
- Niederst, Matthew J
- Mulvey, Hillary E
- Maruvka, Yosef E
- Ji, Fei
- Bhang, Hyo-eun C
- Siravegna, Giulia
- Hu, Haichuan
- Raoof, Sana
- Lockerman, Elizabeth
- Ruddy, David A
- Damon, Leah J
- Crystal, Adam S
- Costa, Carlotta
- Piotrowska, Zofia
- Bardelli, Alberto
- Iafrate, Anthony J
- Sadreyev, Ruslan I
- Stegmeier, Frank
- Getz, Gad
- Sequist, Lecia V
- Faber, Anthony C
- Engelman, Jeffrey A
- Venue
- Nature Medicine
- Published
- 2016-02-01
- Volume
- 22
- Issue
- 3
- Pages
- 262-269
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4900892
- OpenAlex
- W2272802268
- Cited by
- 985
- References
- 55
- Citations by year
- 2026: 73 · 2025: 76 · 2024: 94 · 2023: 104 · 2022: 99 · 2021: 112 · 2020: 94 · 2019: 87 · 2018: 87 · 2017: 92 · 2016: 67
- FWCI
- 99.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA137008)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- EGFR inhibitor resistance, T790M mutation, non-small cell lung cancer, tumor evolution, clonal selection, third-generation EGFR tyrosine kinase inhibitors, navitoclax, Bcl-xL, Bcl-2, apoptosis, acquired drug resistance
- MeSH terms
- Gefitinib, Carcinoma, Non-Small-Cell Lung, Cell Cycle, Cell Survival, Humans, Lung Neoplasms, Mutation, Quinazolines, RNA, Messenger, Blotting, Western, Gene Expression Regulation, Neoplastic, Apoptosis, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Protein Kinase Inhibitors, ErbB Receptors, In Vitro Techniques
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